Interfacial water on collagen nanoribbons by 3D AFM.

Collagen is the most abundant structural protein in mammals. Type I collagen in its fibril form has a characteristic pattern structure that alternates two regions called gap and overlap. The structure and properties of collagens are highly dependent on the water and mineral content of the environment. Here, we apply 3D AFM to characterize at angstrom-scale resolution the interfacial water structure of collagen nanoribbons. For a neutral tip, the interfacial water structure is characterized by the oscillation of the water particle density distribution with a value of 0.3 nm (hydration layers). The interfacial structure does not depend on the collagen region. For a negatively charged tip, the interfacial structure might depend on the collagen region. Hydration layers are observed in overlap regions, while in gap regions, the interfacial solvent structure is dominated by electrostatic interactions. These interactions generate interlayer distances of 0.2 nm.

On the relevance of query definition in the performance of 3D ligand-based virtual screening.

Ligand-based virtual screening (LBVS) methods are widely used to explore the vast chemical space in the search of novel compounds resorting to a variety of properties encoded in 1D, 2D or 3D descriptors. The success of 3D-LBVS is affected by the overlay of molecular pairs, thus making selection of the template compound, search of accessible conformational space and choice of the query conformation to be potential factors that modulate the successful retrieval of actives. This study examines the impact of adopting different choices for the query conformation of the template, paying also attention to the influence exerted by the structural similarity between templates and actives. The analysis is performed using PharmScreen, a 3D LBVS tool that relies on similarity measurements of the hydrophobic/philic pattern of molecules, and Phase Shape, which is based on the alignment of atom triplets followed by refinement of the volume overlap. The study is performed for the original DUD-E+ database and a Morgan Fingerprint filtered version (denoted DUD-E+-Diverse; available in https://github.com/Pharmacelera/Query-models-to-3DLBVS ), which was prepared to minimize the 2D resemblance between template and actives. Although in most cases the query conformation exhibits a mild influence on the overall performance, a critical analysis is made to disclose factors, such as the content of structural features between template and actives and the induction of conformational strain in the template, that underlie the drastic impact of the query definition in the recovery of actives for certain targets. The findings of this research also provide valuable guidance for assisting the selection of the query definition in 3D LBVS campaigns.

Treating Alzheimer's disease using nanoparticle-mediated drug delivery strategies/systems.

The administration of promising medications for the treatment of neurodegenerative disorders (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) is significantly hampered by the blood-brain barrier (BBB). Nanotechnology has recently come to light as a viable strategy for overcoming this obstacle and improving drug delivery to the brain. With a focus on current developments and prospects, this review article examines the use of nanoparticles to overcome the BBB constraints to improve drug therapy for AD The potential for several nanoparticle-based approaches, such as those utilizing lipid-based, polymeric, and inorganic nanoparticles, to enhance drug transport across the BBB are highlighted. To shed insight on their involvement in aiding effective drug transport to the brain, methods of nanoparticle-mediated drug delivery, such as surface modifications, functionalization, and particular targeting ligands, are also investigated. The article also discusses the most recent findings on innovative medication formulations encapsulated within nanoparticles and the therapeutic effects they have shown in both preclinical and clinical testing. This sector has difficulties and restrictions, such as the need for increased safety, scalability, and translation to clinical applications. However, the major emphasis of this review aims to provide insight and contribute to the knowledge of how nanotechnology can potentially revolutionize the worldwide treatment of NDDs, particularly AD, to enhance clinical outcomes.

Oncoplastic breast surgery in Europe.

Oncoplastic breast surgery (OPS) has become an integral part of breast cancer surgery for both breast conservation and mastectomies. In recent years, the emphasis on early detection and the advances in systemic and locoregional therapy has improved prognosis leading to an increased focus on survivorship and quality of life issues including patients' short and long-term aesthetic appearance as a key part of the surgical management. There is a significant variation across Europe in the type of specialist performing breast cancer surgery and the provision of OPS as such. In the traditional model, breast cancer care was provided by gynecologists in some countries, general surgeons, surgical oncologists, and breast surgeons in others. However recently, surgeons throughout Europe have extended their skill-base to include level 1 and 2 OPS and implant- and pedicle-flap based breast reconstruction. For breast surgeons to become proficient in these techniques, a standardized level of training and expertise is needed. The European Society of Mastology (EUSOMA) set standards for a specialist health professional in the field of breast cancer, the European Union of Medical Specialists (UEMS) examinations and the global curriculum that was developed by the American Society of Surgical Oncology (SSO) and the European Society of Surgical Oncology (ESSO) aims to improve standards of OPS practice across Europe. The new generation of breast surgeons, therefore, should be equipped with the necessary skill set to provide high quality OPS while keeping abreast of novel technologies and techniques aiming to provide patients with excellent long-term quality of life.

Membrane Proteome-Wide Screening of Autoantibodies in CIDP Using Human Cell Microarray Technology.

BACKGROUND AND OBJECTIVES: Autoantibody discovery in complex autoimmune diseases is challenging. Diverse successful antigen identification strategies are available, but, so far, have often been unsuccessful, especially in the discovery of protein antigens in which conformational and post-translational modification are critical. Our study assesses the utility of a human membrane and secreted protein microarray technology to detect autoantibodies in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: A cell microarray consisting of human embryonic kidney-293 cells expressing >5,000 human proteins was used. First, a validation step was performed with 4 serum samples from patients with autoimmune nodopathy (AN) to assess the ability of this technology to detect circulating known autoantibodies. The ability of the cell microarray technology to discover novel IgG autoantibodies was assessed incubating the array with 8 CIDP serum samples. Identified autoantibodies were subsequently validated using cell-based assays (CBAs), ELISA, and/or tissue immunohistochemistry and analyzed in a cohort of CIDP and AN (n = 96) and control (n = 100) samples. RESULTS: Serum anti-contactin-1 and anti-neurofascin-155 were detected by the human cell microarray technology. Nine potentially relevant antigens were found in patients with CIDP without other detectable antibodies; confirmation was possible in six of them: ephrin type-A receptor 7 (EPHA7); potassium-transporting ATPase alpha chain 1 and subunit beta (ATP4A/4B); leukemia-inhibitory factor (LIF); and interferon lambda 1, 2, and 3 (IFNL1, IFNL2, IFNL3). Anti-ATP4A/4B and anti-EPHA7 antibodies were detected in patients and controls and considered unrelated to CIDP. Both anti-LIF and anti-IFNL antibodies were found in the same 2 patients and were not detected in any control. Both patients showed the same staining pattern against myelinating fibers of peripheral nerve tissue and of myelinating neuron-Schwann cell cocultures. Clinically relevant correlations could not be established for anti-LIF and anti-IFNL3 antibodies. DISCUSSION: Our work demonstrates the utility of human cell microarray technology to detect known and discover unknown autoantibodies in human serum samples. Despite potential CIDP-associated autoantibodies (anti-LIF and anti-IFNL3) being identified, their clinical and pathogenic relevance needs to be elucidated in bigger cohorts.

Ischemic Complication of a Rare Traumatic True Brachial Artery Aneurysm: A Case Report.

True brachial artery aneurysms are rare. We present the case of a 47-year-old male who was referred to our clinic for the evaluation of progressive right arm claudication. He had suffered a gunshot wound in the right elbow 16 years before his symptoms. Computed tomography angiography revealed a thrombosed true brachial artery aneurysm. The patient was placed in the operating room, and aneurysm resection and reconstruction were performed using an interposition saphenous vein graft. His postoperative period was uneventful, and 1 year after the procedure, he remained asymptomatic. True brachial artery aneurysms associated with remote traumas are rare. This case illustrates the clinical presentation and successful management of arterial reconstruction using an autologous vein graft.

Hybrid hydrogels support neural cell culture development under magnetic actuation at high frequency.

The combination of hydrogels and magnetic nanoparticles, scarcely explored to date, offers a wide range of possibilities for innovative therapies. Herein, we have designed hybrid 3D matrices integrating natural polymers, such as collagen, chitosan (CHI) and hyaluronic acid (HA), to provide soft and flexible 3D networks mimicking the extracellular matrix of natural tissues, and iron oxide nanoparticles (IONPs) that deliver localized heat when exposed to an alternating magnetic field (AMF). First, colloidally stable nanoparticles with a hydrodynamic radius of ∼20 nm were synthesized and coated with either CHI (NPCHI) or HA (NPHA). Then, collagen hydrogels were homogeneously loaded with these coated-IONPs resulting in soft (E0 ∼ 2.6 kPa), biodegradable and magnetically responsive matrices. Polymer-coated IONPs in suspension preserved primary neural cell viability and neural differentiation even at the highest dose (0.1 mg Fe/mL), regardless of the coating, even boosting neuronal interconnectivity at lower doses. Magnetic hydrogels maintained high neural cell viability and sustained the formation of highly interconnected and differentiated neuronal networks. Interestingly, those hydrogels loaded with the highest dose of NPHA (0.25 mgFe/mg polymer) significantly impaired non-neuronal differentiation with respect to those with NPCHI. When evaluated under AMF, cell viability slightly diminished in comparison with control hydrogels magnetically stimulated, but not compared to their counterparts without stimulation. Neuronal differentiation under AMF was only affected on collagen hydrogels with the highest dose of NPHA, while non-neuronal differentiation regained control values. Taken together, NPCHI-loaded hydrogels displayed a superior performance, maybe benefited from their higher nanomechanical fluidity. STATEMENT OF SIGNIFICANCE: Hydrogels and magnetic nanoparticles are undoubtedly useful biomaterials for biomedical applications. Nonetheless, the combination of both has been scarcely explored to date. In this study, we have designed hybrid 3D matrices integrating both components as promising magnetically responsive platforms for neural therapeutics. The resulting collagen scaffolds were soft (E0 ∼ 2.6 kPa) and biodegradable hydrogels with capacity to respond to external magnetic stimuli. Primary neural cells proved to grow on these substrates, preserving high viability and neuronal differentiation percentages even under the application of a high-frequency alternating magnetic field. Importantly, those hydrogels loaded with chitosan-coated iron oxide nanoparticles displayed a superior performance, likely related to their higher nanomechanical fluidity.

Laparoscopic onlay-flap ureteroplasty using cecal appendix.

INTRODUCTION: The management of ureteral strictures longer than 1-2 cm must be treated by major surgery (1, 2). The strictures located at the distal part of the ureter can be managed by a ureteral reimplantation using a psoas hitch or a Boari flap depending on its proximity to the bladder (3). Those located at the proximal ureter can be treated by a pyeloplasty (4). The ureteric strictures in the mid-ureter are the ones that pose a greater challenge for the urologist because a ureteral substitution is needed, either using a segment of the intestine or a buccal mucosa graft (5, 6). Our main objective is to present the management and results at 36 months of a patient with a right mid-ureter stricture. MATERIAL AND METHODS: A 63-year-old male with chronic kidney disease (CKD) and a right single functioning kidney was referred to our department with the diagnosis of a 3 cm stricture in the right mid-ureter. He had a long-term JJ-stent in place but in the last year we had to replace it three times precociously and he even needed the placement of a nephrostomy tube due to the obstruction of the JJ-stent. Accordingly, a permanent resolution was sought and a laparoscopic onlay-flap ureteroplasty using cecal appendix was performed. RESULTS: The first step was to identify the cecal appendix. Then we identified and dissected the ureter. With the ureter dissected, we performed a ureteroscopy to pinpoint the stricture. Once we knew where the stricture was, we proceeded with the ureterotomy and preparation of the cecal appendix. The final step was to perform the ureteroplasty between the ureter and the cecal appendix placing a JJ-stent before the last stitches were done. Total operative time was 190 minutes without any intraoperative complication. The JJ-stent was removed 7 weeks later. The follow-up of the patient was done with regular blood test and ultrasound to rule out deterioration of the CKD and worsening of the residual hydronephrosis. With a follow-up of 36 months, the patient is stent free, he hasn't had any further intervention and neither the CKD nor the hydronephrosis haven't worsened. CONCLUSIONS: Laparoscopic onlay-flap ureteroplasty using cecal appendix is a feasible and well tolerated procedure for patients with right mid-ureter stricture. However, we must bear in mind the difficulty of these cases and they should be performed in expert centers.

Generalized anosognosia, anosodiaphoria, and visual hallucinations with bilateral enucleation after severe bifrontal brain injury: a case report describing similarities with and differences from Anton syndrome.

Visual anosognosia, associated with confabulations and cortical blindness in the context of occipital lobe injury, is known as Anton syndrome. Patients with this syndrome strongly deny their vision loss and confabulate to compensate for both visual loss and memory impairments. In this article, we present a case of a patient with some similarities to Anton syndrome, however, with several differences in clinical presentation. Bifrontal brain injury, bilateral enucleation, affective indifference (anosodiaphoria), generalized anosognosia, and the conviction that vision will resume mark clear clinical differences with Anton syndrome. Differentiating these findings from Anton syndrome will help occupational therapists, neuropsychologists, speech-language pathologists, physical therapists, and physicians when assessing frontal lobe brain injury with total and partial visual loss. This case demonstrates that visual anosognosia and confabulations can occur without occipital lobe dysfunction or cortical blindness.

Physical activity and its relationship to burden and health concerns in family caregivers of people with dementia.

BACKGROUND: Caring for people with dementia (PwD) usually triggers stress and leads to mental and somatic health complaints (SHCs). Physical activity (PA) can provide burden relief in PwD caregivers, but it is not clear whether PA habits would contribute to reducing SHCs. This study aims to analyze the effect of PA on the relationship between burden and SHCs in a sample of family caregivers of PwD. METHODS: One hundred and fifty-seven caregivers of PwD reported their PA habits, and completed the Giessen's Subjective Health Complaints Questionnaire (GBB-8) and the Zarit Burden Interview (ZBI). The relationship between PA habits, burden of care (ZBI), and SHCs (B-GBB-8 scale) was examined. Subsequently, the moderating effect of PA habits on the relationship between burden and SHCs was tested. RESULTS: PA habit was inversely associated with ZBI (rbp = -0.242) and GBB-8 scores (rbp (Gastrointestinal) = -0.174; rbp (Musculoskeletal) = -0.195; rbp (Exhaustion) = -0.247; rbp (Cardiovascular) = -0.250; and rbp (Overall) = -0.257, respectively), whereas moderate positive correlations were found between ZBI and GBB-8 scores (r (Gastrointestinal) = 0.483; r (Musculoskeletal) = 0.536; r (Exhaustion) = 0.542; r (Cardiovascular) = 0.438; and r (Overall) = 0.598, respectively). The interaction effect of PA habit and burden was significant for the overall SHCs (b = -0.11; P < 0.05) and cardiovascular complaints (b = -0.06; P < 0.05). However, the association between burden and SHCs was significant (P < 0.001) only for sedentary caregivers. CONCLUSION: These findings indicate that maintaining an active lifestyle through regular PA could potentially help alleviate the adverse effects of caregiver burden on somatic health among caregivers of PwD. Encouraging and endorsing PA interventions for informal caregivers might yield substantial advantages for their health and general well-being.

Age of autism diagnosis in Latin American and Caribbean countries.

LAY ABSTRACT: An earlier diagnosis of autism spectrum disorder might lead to earlier intervention. However, people living in Latin American and Caribbean countries do not have much knowledge about autism spectrum disorder symptoms. It has been suggested that the older a child is when diagnosed, the fewer opportunities he or she will have to receive services. We asked 2520 caregivers of autistic children in six different Latin America and Caribbean Countries, the child's age when they noticed some developmental delays and their child's age when they received their first autism spectrum disorder diagnosis. Results indicate that, on average, caregivers were concerned about their child's development by 22 months of age; however, the diagnosis was received when the child was 46 months of age. In addition, older children with better language abilities and public health coverage (opposed to private health coverage) were diagnosed later. On the contrary, children with other medical problems and more severe behaviors received an earlier diagnosis. In our study, children were diagnosed around the time they entered formal schooling, delaying the access to early intervention programs. In summary, the characteristics of the autistic person and the type of health coverage influence the age of diagnosis in children living in Latin America and Caribbean Countries.

Nanorheology and Nanoindentation Revealed a Softening and an Increased Viscous Fluidity of Adherent Mammalian Cells upon Increasing the Frequency.

The nanomechanical response of a cell depends on the frequency at which the cell is probed. The components of the cell that contribute to this property and their interplay are not well understood. Here, two force microscopy methods are integrated to characterize the frequency and/or the velocity-dependent properties of living cells. It is shown on HeLa and fibroblasts, that cells soften and fluidize upon increasing the frequency or the velocity of the deformation. This property was independent of the type and values (25 or 1000 nm) of the deformation. At low frequencies (2-10 Hz) or velocities (1-10 µm s-1 ), the response is dominated by the mechanical properties of the cell surface. At higher frequencies (>10 Hz) or velocities (>10 µm s-1 ), the response is dominated by the hydrodynamic drag of the cytosol. Softening and fluidization does not seem to involve any structural remodeling. It reflects a redistribution of the applied stress between the solid and liquid-like elements of the cell as the frequency or the velocity is changed. The data indicates that the quasistatic mechanical properties of a cell featuring a cytoskeleton pathology might be mimicked by the response of a non-pathological cell which is probed at a high frequency.

Lavandula pedunculata Polyphenol-Rich Extracts Obtained by Conventional, MAE and UAE Methods: Exploring the Bioactive Potential and Safety for Use a Medicine Plant as Food and Nutraceutical Ingredient.

Nowadays, plant-based bioactive compounds (BCs) are a key focus of research, supporting sustainable food production and favored by consumers for their perceived safety and health advantages over synthetic options. Lavandula pedunculata (LP) is a Portuguese, native species relevant to the bioeconomy that can be useful as a source of natural BCs, mainly phenolic compounds. This study compared LP polyphenol-rich extracts from conventional maceration extraction (CE), microwave and ultrasound-assisted extraction (MAE and UAE). As a result, rosmarinic acid (58.68-48.27 mg/g DE) and salvianolic acid B (43.19-40.09 mg/g DE) were the most representative phenolic compounds in the LP extracts. The three methods exhibited high antioxidant activity, highlighting the ORAC (1306.0 to 1765.5 mg Trolox equivalents (TE)/g DE) results. In addition, the extracts obtained with MAE and CE showed outstanding growth inhibition for B. cereus, S. aureus, E. coli, S. enterica and P. aeruginosa (>50%, at 10 mg/mL). The MAE extract showed the lowest IC50 (0.98 mg DE/mL) for angiotensin-converting enzyme inhibition and the best results for α-glucosidase and tyrosinase inhibition (at 5 mg/mL, the inhibition was 87 and 73%, respectively). The LP polyphenol-rich extracts were also safe on caco-2 intestinal cells, and no mutagenicity was detected. The UAE had lower efficiency in obtaining LP polyphenol-rich extracts. MAE equaled CE's efficiency, saving time and energy. LP shows potential as a sustainable raw material, allowing diverse extraction methods to safely develop health-promoting food and nutraceutical ingredients.

Fast and high-resolution mapping of van der Waals forces of 2D materials interfaces with bimodal AFM.

High-spatial resolution mapping of van der Waals forces is relevant in several fields ranging from nanotechnology to colloidal science. The emergence of two-dimensional heterostructures assembled by van der Waals interactions has enhanced the interest of those measurements. Several AFM methods have been developed to measure the adhesion force between an AFM probe and the material of interest. However, a reliable and high-resolution method to measure the Hamaker constant remains elusive. We demonstrate that an atomic force microscope operated in a bimodal configuration enables fast, quantitative, and high-resolution mapping of the Hamaker constant of interfaces. The method is applied to map the Hamaker constant of monolayer, bilayer and multilayer MoS2 surfaces. Those interfaces are characterized with Hamaker constant and spatial resolutions of, respectively, 0.1 eV and 50 nm.

Participatory ethnobotany: comparison between two quilombos in the Atlantic Forest, Ubatuba, São Paulo, Brazil.

Ethnobotanical studies that use the participatory research approach seek to involve the residents of a community in different stages of the study, promoting the registration, dissemination and strengthening of local knowledge, as well as the empowerment of decisions related to the sustainable use and management of resources. Using the participatory methodology, this study recorded and made a comparative analysis on the use of plants in two quilombola communities (Quilombo do Cambury-QC and Quilombo da Fazenda-QF) in the State of São Paulo. After a training on anthropological and botanical methods, local researchers selected and interviewed the local experts, recording their knowledge on plant uses and collecting the indicated plants, to be identified and deposited in herbariums. In addition, participant observation and field diaries were used by the academic researchers, helping to analyze the data. To test the differences in the composition of species known to local community, a Jaccard dissimilarity matrix was created, and a Permanova test was employed. During the 178 days of fieldwork, three local researchers from the QC and two from the QF, selected nine and eight experts on the uses of the plants in each quilombo, respectively, corresponding to 214 plant species, indicated for eight ethnobotanical categories. Our hypothesis has been confirmed, since the traditional knowledge found in both quilombos, regarding plant uses and the number of plant species by category, are distinct, since each community occupies particular plant areas and different phytophysiognomies. Most of the indicated species are native to the Atlantic forest, and no significant differences were observed in the proportion of native species vs. introduced among quilombos for any of the categories of use studied. Furthermore, the innovative methodology used, participatory ethnobotany, contributed to the empowerment of community members with regard to the use of their available resources in the environment in which they live, while retaining the intellectual property rights over their own knowledge.

Summer and spring elbow rashes is a variant of polymorphous light eruption: confirmation by photoprovocation and histopathology in a series of five cases.

Background: Summer and spring eruptions on the elbows are a variant of polymorphous light eruption described on clinical and histopathological grounds; however, to our knowledge, they have not been confirmed by photobiological studies. Objective: Based on photobiological studies, this study aimed to demonstrate the involvement of ultraviolet-A (UVA) radiation in this variant of polymorphous light eruption occurring exclusively on the elbows. Methods: A series of five patients with polymorphous light eruption lesions on the elbows were included in our study. All patients underwent phototesting and photoprovocation of the skin lesions after exposure to a UVA light source [Philips UVA HPA lamp (400 W)]. All patients underwent punch biopsy and histopathological and immunohistochemical studies with anti-CD123. Results: In all the cases, UVA irradiation caused the appearance of skin lesions on the elbows with characteristic polymorphous light eruption. Histological data showed edema in the superficial dermis and a perivascular lymphocytic infiltrate compatible with polymorphous light eruption. Immunohistochemical staining for CD1-23 showed negative results. Conclusions: For the first time, photobiological photoprovocation studies demonstrated that repeated exposure to UVA radiation leads to the generation of skin lesions on the elbows, which are clinically and histologically consistent with summer and spring eruptions, confirming that elbow rash is a variant of polymorphous light eruption.

In planta expression of human polyQ-expanded huntingtin fragment reveals mechanisms to prevent disease-related protein aggregation.

In humans, aggregation of polyglutamine repeat (polyQ) proteins causes disorders such as Huntington's disease. Although plants express hundreds of polyQ-containing proteins, no pathologies arising from polyQ aggregation have been reported. To investigate this phenomenon, we expressed an aggregation-prone fragment of human huntingtin (HTT) with an expanded polyQ stretch (Q69) in Arabidopsis thaliana plants. In contrast to animal models, we find that Arabidopsis sp. suppresses Q69 aggregation through chloroplast proteostasis. Inhibition of chloroplast proteostasis diminishes the capacity of plants to prevent cytosolic Q69 aggregation. Moreover, endogenous polyQ-containing proteins also aggregate on chloroplast dysfunction. We find that Q69 interacts with the chloroplast stromal processing peptidase (SPP). Synthetic Arabidopsis SPP prevents polyQ-expanded HTT aggregation in human cells. Likewise, ectopic SPP expression in Caenorhabditis elegans reduces neuronal Q67 aggregation and subsequent neurotoxicity. Our findings suggest that synthetic plant proteins, such as SPP, hold therapeutic potential for polyQ disorders and other age-related diseases involving protein aggregation.